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An alcoholic extract of Thuja orientalis L. leaves inhibits autophagy by specifically targeting pro-autophagy PIK3C3/VPS34 complex

Autophagy is a lysosome-dependent degradation program to maintain cellular homeostasis in response to a variety of stressful conditions, such as long-lived or non-functional subcellular organelles, protein aggregates, nutrient limitation, and virus/bacteria infection. Accordingly, dysregulation of a...

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Autores principales: Jung, Juneyoung, Chun, Yoomi, Jang, Young Pyo, Oh, Myung Sook, Kim, Jeong Hee, Kim, Joungmok
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421415/
https://www.ncbi.nlm.nih.gov/pubmed/34489486
http://dx.doi.org/10.1038/s41598-021-97216-4
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author Jung, Juneyoung
Chun, Yoomi
Jang, Young Pyo
Oh, Myung Sook
Kim, Jeong Hee
Kim, Joungmok
author_facet Jung, Juneyoung
Chun, Yoomi
Jang, Young Pyo
Oh, Myung Sook
Kim, Jeong Hee
Kim, Joungmok
author_sort Jung, Juneyoung
collection PubMed
description Autophagy is a lysosome-dependent degradation program to maintain cellular homeostasis in response to a variety of stressful conditions, such as long-lived or non-functional subcellular organelles, protein aggregates, nutrient limitation, and virus/bacteria infection. Accordingly, dysregulation of autophagy is closely associated with many human pathophysiological conditions, such as neurodegenerative diseases, aging, and cancer, and autophagy is highlighted as an important therapeutic target for these human diseases. In autophagy process, PIK3C3/VPS34 complex plays important roles in autophagosome biogenesis. Accumulating evidences that inhibition of PIK3C3/VPS34 complex successfully blocks autophagy make the complex as an attractive target for the development of autophagy-specific inhibitors. However, considering that various forms of PIK3C3/VPS34 complex exist and they are involved in many different cellular functions, the targeting of the pro-autophagy PIK3C3/VPS34 complex is required to specifically inhibit autophagy. To identify autophagy inhibitors targeting the pro-autophagy complex, we have performed the screening of a customized natural product library consisting of 35 herbal extracts which are widely used in the oriental medicine as anti-inflammation and/or anti-tumor reagents. We discovered that an alcoholic extract of Thuja orientalis L. leaves inhibits pro-autophagy complex formation by disrupting the interaction between autophagy-specific factor, ATG14L, and the complex core unit Vps34-Beclin 1 in vitro. Also, it inhibits the nutrient starvation induced autophagy and diminished pro-autophagy PIK3C3/VPS34 complex containing either ATG14L or UVRAG in several cell lines. Our results strongly suggest that Thuja orientalis L. leave extract functions as an autophagy-specific inhibitor not decreasing the complex activity nor the protein level, but preventing protein–protein interaction between autophagy-specific factor (ATG14L and UVRAG) and PIK3C3/VPS34 complex core unit, Vps34-Beclin 1, thereby specifically depleting the pro-autophagy complex to inhibit autophagy.
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spelling pubmed-84214152021-09-09 An alcoholic extract of Thuja orientalis L. leaves inhibits autophagy by specifically targeting pro-autophagy PIK3C3/VPS34 complex Jung, Juneyoung Chun, Yoomi Jang, Young Pyo Oh, Myung Sook Kim, Jeong Hee Kim, Joungmok Sci Rep Article Autophagy is a lysosome-dependent degradation program to maintain cellular homeostasis in response to a variety of stressful conditions, such as long-lived or non-functional subcellular organelles, protein aggregates, nutrient limitation, and virus/bacteria infection. Accordingly, dysregulation of autophagy is closely associated with many human pathophysiological conditions, such as neurodegenerative diseases, aging, and cancer, and autophagy is highlighted as an important therapeutic target for these human diseases. In autophagy process, PIK3C3/VPS34 complex plays important roles in autophagosome biogenesis. Accumulating evidences that inhibition of PIK3C3/VPS34 complex successfully blocks autophagy make the complex as an attractive target for the development of autophagy-specific inhibitors. However, considering that various forms of PIK3C3/VPS34 complex exist and they are involved in many different cellular functions, the targeting of the pro-autophagy PIK3C3/VPS34 complex is required to specifically inhibit autophagy. To identify autophagy inhibitors targeting the pro-autophagy complex, we have performed the screening of a customized natural product library consisting of 35 herbal extracts which are widely used in the oriental medicine as anti-inflammation and/or anti-tumor reagents. We discovered that an alcoholic extract of Thuja orientalis L. leaves inhibits pro-autophagy complex formation by disrupting the interaction between autophagy-specific factor, ATG14L, and the complex core unit Vps34-Beclin 1 in vitro. Also, it inhibits the nutrient starvation induced autophagy and diminished pro-autophagy PIK3C3/VPS34 complex containing either ATG14L or UVRAG in several cell lines. Our results strongly suggest that Thuja orientalis L. leave extract functions as an autophagy-specific inhibitor not decreasing the complex activity nor the protein level, but preventing protein–protein interaction between autophagy-specific factor (ATG14L and UVRAG) and PIK3C3/VPS34 complex core unit, Vps34-Beclin 1, thereby specifically depleting the pro-autophagy complex to inhibit autophagy. Nature Publishing Group UK 2021-09-06 /pmc/articles/PMC8421415/ /pubmed/34489486 http://dx.doi.org/10.1038/s41598-021-97216-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Jung, Juneyoung
Chun, Yoomi
Jang, Young Pyo
Oh, Myung Sook
Kim, Jeong Hee
Kim, Joungmok
An alcoholic extract of Thuja orientalis L. leaves inhibits autophagy by specifically targeting pro-autophagy PIK3C3/VPS34 complex
title An alcoholic extract of Thuja orientalis L. leaves inhibits autophagy by specifically targeting pro-autophagy PIK3C3/VPS34 complex
title_full An alcoholic extract of Thuja orientalis L. leaves inhibits autophagy by specifically targeting pro-autophagy PIK3C3/VPS34 complex
title_fullStr An alcoholic extract of Thuja orientalis L. leaves inhibits autophagy by specifically targeting pro-autophagy PIK3C3/VPS34 complex
title_full_unstemmed An alcoholic extract of Thuja orientalis L. leaves inhibits autophagy by specifically targeting pro-autophagy PIK3C3/VPS34 complex
title_short An alcoholic extract of Thuja orientalis L. leaves inhibits autophagy by specifically targeting pro-autophagy PIK3C3/VPS34 complex
title_sort alcoholic extract of thuja orientalis l. leaves inhibits autophagy by specifically targeting pro-autophagy pik3c3/vps34 complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421415/
https://www.ncbi.nlm.nih.gov/pubmed/34489486
http://dx.doi.org/10.1038/s41598-021-97216-4
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